title: Association of TCF7L2 SNPs with age at onset of type 2 diabetes and proinsulin/insulin ratio but not with glucagon-like peptide 1.
abstract: BACKGROUND
  Variants in TCF7L2 have been associated with the age at onset of type 2 diabetes in Mexican Americans. However, there is a lack of data on this relationship in Caucasians. Furthermore, risk alleles in TCF7L2 have been suggested to account for decreased conversion of proinsulin to insulin and decreased expression of GLP-1. We investigated the effect of the allelic variants rs1225537 and rs7903146 in TCF7L2 on the age at onset of type 2 diabetes, the plasma concentrations of proinsulin and GLP-1, and the ratio of proinsulin to insulin in a German cohort.
  
  
  METHODS
  We studied 3185 participants of the LUdwigshafen RIsk and Cardiovascular health (LURIC) study. Among these, 1021 subjects had type 2 diabetes. Data on age at onset of diabetes were available in 925 subjects. OGTTs were performed in a subgroup not previously known to have diabetes.
  
  
  RESULTS
  Carriers of the risk alleles in rs1225537 and rs7901346 had increased risk of type 2 diabetes and elevated HbA(1c) (all p < 0.001). The risk alleles were also associated with early onset of type 2 diabetes, decreased insulin secretion and markedly increased proinsulin and proinsulin to insulin ratio (all p < 0.03). GLP-1 was not significantly related to the TCF7L2 genotype.
  
  
  CONCLUSIONS
  Our data demonstrate that TCF7L2 variants are associated with an early age of onset of type 2 diabetes in Caucasians and affects the conversion of proinsulin to insulin. However, TCF7L2 is not consistently associated with fasting GLP-1.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease, and Clinical Chemistry, Eberhard-Karls-University Tübingen, Tübingen, Germany.
authors.forename: Guenther
authors.initials: G
authors.lastname: Silbernagel
authors.forename: Wilfried
authors.initials: W
authors.lastname: Renner
authors.forename: Tanja B
authors.initials: TB
authors.lastname: Grammer
authors.forename: Sigrun R
authors.initials: SR
authors.lastname: Hügl
authors.forename: Julia
authors.initials: J
authors.lastname: Bertram
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Kleber
authors.forename: Michael M
authors.initials: MM
authors.lastname: Hoffmann
authors.forename: Bernhard R
authors.initials: BR
authors.lastname: Winkelmann
authors.forename: Winfried
authors.initials: W
authors.lastname: März
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
mesh_terms: D017668:Age of Onset; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000097:blood*; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007328:Insulin / Q000097:blood* / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011384:Proinsulin / Q000097:blood*; D012306:Risk; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007328:Insulin; D011384:Proinsulin; D058118:Transcription Factor 7-Like 2 Protein; C544894:TCF7L2 protein, human; C517652:hemoglobin A1c protein, human